DE2033145A1 - Sulfur-containing pyrimidine derivatives and their preparation and use - Google Patents

Description

Sulfur-containing pyrimidine derivatives and their preparation

and use

The present invention relates to compounds that have therapeutic, in particular anti-inflammatory, properties. *

These compounds are those outlined in the attached Pig. 1 fall under the general formula (I) in which η is an integer, namely 2 or 3j

R is a hydrogen atom or forms a double bond with R 1; R _{1 is} hydrogen or lower alkyl; Rp and R. each represent a hydrogen atom, a lower alkyl radical, a phenyl radical optionally substituted by halogen, a nitro, hydroxyl, carboxyl, halosulfonyl, trifluoromethyl, lower alkyl, lower alkoxy, lower carbalkoxyalkyl or lower alkanylamido radical or is an aromatic heterocyclic radical and R * is a hydroxyl group or forms a double bond with R, as well as their addition salts with acids, in particular pharmaceutically acceptable acids

009883/2272

In the definition above, a lower alkyl or alkoxy radical is understood to mean a best with 1-4 carbon atoms. " Likewise are among lower carbalkoxyalkyl and alkanylamido radicals those to understand, those in their hydrocarbon content or have 1-4 carbon atoms in each of their hydrocarbon components.

The compounds (I) are characterized in that η 2 or 3 is that the thiazoline pyrimidines are in the 5 and / or 7 position are substituted, or that the thiazidine pyrimidines ■ in 6- and / or 8-position are substituted »

To prepare the compounds (I), it is possible to refer to that explained in FIG Procedure referenced.

This process consists of the condensation of a sulfur-containing heterocyclic imine of the general formula

(ID

(CHj

2 'η

with 'a (^ .- unsaturated carbonyl compound of the general formula

R ₉ - C »CH - G - HE ₁ O

in which n, I ₁ JE ₂ and E ^ have the above conditions, and optionally subsequent reaction with an acid to a salt of the resulting Vertoindtang (I) »

009883/2212

The imine (II) can be in free form or in the form of its salt be used.

In the latter case, the imine is replaced by an alkaline compound released in situ.

This condensation is advantageous in an organic solvent, such as acetone, chloroform, ethanol, xylene or a mixture of two or more of these.

The procedures used start with the hydroxyl compounds (Ia) in which R 1 is a hydroxyl group, or of the compounds (Ib) obtained by dehydration of the the former have arisen, and in which E and R, together one Form double bond.

The compounds (Ia) according to scheme (a) of FIG. 2, in_xlem the condensation temperature, like the ambient temperature, is lowered or is changed.

The compounds (Ib) are obtained according to the scheme (b) in Fig. 2 by the condensation temperature is more increased, preferably to about 7O ⁰ C.

Since it is convenient, the condensation under reflux of the solvent carry out, one chooses a solvent in this case with a high boiling point, such as ethanol or xylene.

0098 83/227 2

_4- 7033H5 '

On the other hand, it is possible, through the action of the temperature (see (c)), to convert the compounds (Ia) into the compounds (Ib) to convert by hydration «For this purpose, a salt of the compound (a), such as the chlorohydrate, is advantageously used for Dehydration. This salt is melted in the absence of air, namely in a solvent with a high

and

depoint, such as propylene glycol, under reflux of this solvent heated.

The following examples illustrate the invention. example 1

Preparation of 5,7-diphenyl-2,3,5-trihydro- (3,2a) thiazolpyrimidine (Formula I: n = 2, R ₁ = H, R ₂ = CgH ^ -, R + -R = double bond, R . = CgHj-; Code No. 523).

In a 250 ml flask is passed benzalacetone 0.2 mol or chalcone (III: R ₂ = CGH, R ₁ = H, R = ^C 6 ^H 5 ~) ^{and a} ° ^{"2 Mo1} ethanolic solution of 2-imino thiazolidine (II, η = 2). It is refluxed for 3 hours. It is then left to stand overnight at room temperature and the crystalline product is air-dried. It is recrystallized in ethyl alcohol, left to air dry and dried over potassium oxide. 16.2 g of a pale yellow product with a melting point are obtained

ο
from 133 - 140 C.

Total nitrogen basic nitrogen

cal. ■ 9.58 4.79

found 9 * 64 4.78

009883/2272

20331-5

Example 2

Preparation of 6,8-diphenyl-2,3,4,6-tetrahydro-1,3-thiazine- (3,2a) pyrimidine (formula I: η = 3, R ₁ = H, R ₂ = CgH ₅ , R + R ^ = double bond, R ₄ = GgH ₅ ; code no. 526).

20 g of 2-imino-metathiazine bromohydrate (II: η = 3) and 5.4 g of sodium methylate are introduced into 50 ml of methanol. It is filtered to remove the sodium bromide that has formed. A benzalacetophenone solution (III: R ₂ = CgH ₅ -, R ₁ = H, R ₄ = CgH ₅ -) in chloroform is added. The mixture is stirred for 5 hours with the exclusion of light. It is concentrated in a rotary evaporator and left to stand in an ice bath for 2 hours. It is air-dried and recrystallized from an ethanol-chloroform mixture. 7 »2 g of a pale pink product with a melting point of

156 ⁰ C. Analysis: Total nitrogen basic stick
material ber. ia 9.15 4.58 found ok 9.01 4.61 Example 3

Preparation of 5-phenyl-7-hydroxy-7 (m-trifluoromethylphenyl) -2,3,5,6-tetrahydro (3,2a) -thiazol-pyrimidine (formula I: η = 2, R ₁ = \ H, R ₂ = C ₆ H ₅ , R = ■ H, R ₅ = OH, R ₄ = Ia-CE ₃ -GgH | code no »530), ν

An acetoric solution of 22 g of benzal (trifluoromethyl-3 ') acetophenone (III: R ₂ = CgH ₅ , Ε _χ = H, R. = m-CF 3 -CgH _{4 ) is} mixed with an acetone solution of 8 g of 2 -Imino-thiazolidine

009883/2272

"2033H5

(II: η = 2). It is stirred and then left to stand for one night. The crystals formed are then washed with acetone and dried over potassium oxide. This gives 20 g of white product with a melting point of 132-141 ⁰ C.

Analysis:

ber. i » gef. $>

Total nitrogen

7.40
7.47

basic nitrogen

3.70 3.71

Example 4

Preparation of 5- (2'-bromophenyl) -7-hydroxy-7-phenyl-2,3,5,6-tetrahydro- (3,2a) thiazol-pyrimidine (formula I: η = 2, R ₁ = H, R ₂ = O-Br-C ₆ H ₄ , E = H, R ₅ = OH, R ₄ = CgH (Oode No. 572).

14.3 g of 2-bromo-benzalacetophenone (III: R ₃ = o-Br-CgH, R ₁ = H, R = C ₆ H ₅ ) and 5.1 g of 2-imino are added to 100 ml of acetone with stirring -thiazolidine (II: η = 2). Crystallization begins after an hour. Stirring is continued for two hours and then left to stand for 36 hours. It is air-dried, washed with acetone and ether and then dried. 11 g of the product with a melting point of 114-117 ° C. are obtained.

Analysis:

about »^ gef» &

Total nitrogen basic nitrogen

7.19
7.16

3.59 3.56

Example 5

Production of 5-phenyl-7- (m-chlorophenyl) -2 _s 3,5-trihydro-

009883/2 272

(3t2a) thlazol-pyrimidine (formula Ir η '= 2, R ₁ = H, R ₂ = CgfiL · »R + r_ = double bond, R ₄ = m-Cl-CgHj; code no. 542).

a) Preparation of 5-phenyl-7-hydroxy-7 (m-chlorophenyl) -2.3> 5f 6-tetrahydro (3t2a) thiazol-pyrimidine (formula Ii η = 2, R ₁ = H, R ₂ = C ₆ H, R = H, R ₅ = OH, R ₄ = m-Cl-CgH ^; Code No. 537).

One collects 0.1 mol of ^ '- benzal-chloroacetophenone (III: R ₂ = ^c gHc> R, = H, R. = m-Cl-CgH,), dissolved in acetone, and 0.1 mol of 2-iminothiazolidine ( Hi η = 2), also dissolved in acetone. The mixture is stirred for an hour and allowed to stand for a quay. The crystals formed are air-dried, washed in acetone and dried. 27 g of a white product with a melting point of 125 ° -130 ° C. are obtained

Analysis; Total nitrogen basic nitrogen

Calc. $ 8.10 4.05

found £ 8.20 4.14

; -; . ^: "b) Production of the chlorohydrate3.

A suspension of 0.15 mol of that obtained according to a) is prepared hydroxylated product in 50 ml of chloroform, and 60 ml of ethanol here. Hydrogen chloride gas is passed in until saturation is reached. Most of the solvent is then removed. An oily residue is obtained.

c) Preparation of S- (3t2a) -thiazol-pyrimidine. · ·

The oily residue obtained according to b) is heated to 230 ° C. for 45 minutes

00988372272

■■, ORIGINAL INSPECTED

placed under exclusion of air on a Darcet alloy bath. The mixture is allowed to cool with the exclusion of air and is taken up with 150 ml of chloroform and excess soda with stirring. After two liquid phases have been obtained, it is decanted and the chloroform is collected, which is dried over sodium sulfate and evaporated to dryness. The residue is taken up with 200 ml of warm methanol. It is filtered, allowed to cool for 48 hours, allowed to air dry, washed with alcohol and then recrystallized from methanol. This gives 15.5 g of the pale yellow product having a melting point of 95 - 11O ^{0 C.;} . '

Analysis; Total nitrogen basic nitrogen

calculated% 8.57 4.28

found io 8.47 4.45

In the following table are the constitution and the physical Properties obtained according to the above examples Compounds (I) and other compounds (i) obtained in a similar manner. In this table, also the anti-inflammatory effect of the compounds (I) as determined by the following test.

Rats received a single injection by the intraplantar route, 1 mg of carrageenin in 0.1 ml of water. The one to be tested Compound (I) is administered orally in an amount of '30 up to 100 mg per kg half an hour before the carrageenin.

The extent of the rat's foot is measured by plethysmometry

009883/2272

Measured 2 hours after the injection of the carrageenin and man compares the obtained values with a comparative animal which has not received the compound (I).

The anti-inflammatory effects of the compound (I), viz
its ability to reduce the edema caused by Garragenin is expressed by 1-4 crosses; 4 crosses
represent the maximum of the anti-inflammatory effect.

0098 83/22 72

n ⁸ I. ^E 2 H OH ^R 4 Melting point
⁰ C Code no. inflammatory
inhibiting
activity 2 H ° 6 ^H 5 H OH ^C 6 ^H 5 111-115 CVJ H ° 6 ^H 5 Double bond H 160-161 469 2 H ° 6 ^H 5 Double bond 133-140 481 009883 H ° 6 ^H 5 H OH ο 5 156 523 ro 3 H ° 6 ^H 5 H'OH H 156 526 + ' • «j""
to CVJ H ° 6 ^H ₅ H OH In-CF ₃ -C ₆ H ₄ 132-141 529 CVJ CH ₃ H OH CH ₃ 145-148 530 * 2 H . ( 0-01-O ₆ H ₄ Double bond ^C 6 ^H 5 111-117 531 2 H ° 6 ^H 5 H OH Hi-CF ₃ -C ₆ H ₄ 98-103 532 2 H. ° 6 ^H 5 CH ₃ 129-134 533 ⁺ 535

TO CD CO OO

η R ₁ H R _p R. R ' R ₄ OH Hh Melting point Code no. inflammatory
inhibiting X H C. j OH ^C 6 ^H 5 ⁰ C activity 2 H Hh H OH In-Cl-C ₆ H ₄ OH In-C ₂ H ₅ OC ₆ H ₄ 125-130 537 Λ 2 H P-CH ₅ OC ₆ H ₄ H OH ^C 6 ^H 5 OH ^C 6 ^H 5 110-115 538 > CD CM H CH ₅ H OH H 138-140 539 ': ν ■' ... O
CO
OO 2 H ^C 6 ^H 5 Double bond K-Gl-CgH ₄ 95-110 542 ++ ■ + co
co 2 H 0-Cl-C ₆ H ₄ Double bond ^ fi ^ S 115-130 543 ₊₊ ro
ro. 2 H P-CH ₅ OC ₆ H ₄ Double bond ^c sh 105-110 545 ₊₊ to 2 H P-Cl-C ₆ H ₄ H 104-107 546 ₊₊₊ 2 H In-Cl-C ₆ H ₄ H 98-100 547 2 ^C 6 ^H 5 H 100-105 551 ⁺ 2 2'-thienyl H 100-105 560

CD CO CO

η ^R l ^R 2 RR ₅ ^R 4 Melting point Code-ur. inflammation s-
inhibiting I. ⁰ C activity IV)
I. CVl H H H OH CH ₅ 131-133 562 * 2 H P-CH ₅ -C ₆ H ₄ Double bond ^C 6 ^H 5 138-146 566 * 2 H O-Br-C ₆ H ₄ H OH ^C 6 ^H 5 114-117 572 TO 860 2 H ^C 6 ^H 5 H OH P-Br-C ₆ H ₄ 138-139 576 ~. 033 W.
OO 2 H ^C 6 ^H 5 Double bond P-Br-C ₆ H ₄ 169-174 577 ♦ + ! S3
to 2 H O ₆ H ₅ Double bond CH ₅ 155-140 563 + IV) H ο -Br-C ^ -H.
6 4 Double bond ^C 6 ^H 5 132-138 582 ♦♦ 2 H ° 6 ^H 5 Double binding 2'-thienyl 155 592 ₊₊₊ 2 H ° 6 ^H 5 H OH 3'-CH, CONH-C, - H ₄ 145-150 597 «■ 2 H ° 6 ^H 5 H OH 3'-pyridyl 115-117 598 2 H · ° 6 ^H 5 H OH 3'-NO ₂ -C ₆ H ₄ 144-146 599 *

Melting point Code-Mr inflammatory

—_ __ inhibitory

activity

3'-pyridyl H.

OH

^C 6 ^H 5 105-108

604

° 6 ^Η

gx *, - double bond 2'-HOOC-CgH ₄

210

610

^Ο 6 ^Η 5

Double bond 4'-HO-CgH ₄ . • 611

^Ο 6 ^Η 5

Double bond 158-159

613

^Ο 6 ^Η 5

Double weave 3 '-C

615

H 3 ', 4', 5 '- (CH ₅ O) ₅ - double

^C 6 ^H 5 98-99

C ^ H

6 ^ 2

binding 617

^Ο 6 ^Η 5

OH 3 • -PO ₂ S-CgH ₄ '150-152

640

O ₆ H ₅ double bond 4'-C ₂ H ₅ OCOCH ₂ -648

^Ο 6 ^Η 5

Double bond 3'-PO ₂ S-CgH ₄ 152-153 650

H 2'-ihienyl double bond

^C 6 ^H 5 125-133

652

^σ 6 ^Η 5

Double bond 3 • -MO ₂ -C5H ₄ 114-116 675

2033H5

In view of their anti-inflammatory effects, these compounds are suitable as therapeutics for humans. she can be administered for this purpose in one of the classic ways, in this case in admixture with the usual routes for this Appropriate binders. The suitable daily dose is generally between 300 and 1500 mg. It is so that the compounds (I) can be in particular in tablet form and in the form of suppositories, each 50-300 mg of the active compound, and administered in accordance with the above-mentioned dose in several servings daily can be.

009883/2 272

Claims (1)

X, sulfur-containing pyrimidine derivative of the general formula (I) (CH ₀ ) η in the η is an integer, and z, var is 2 or 3; R is a hydrogen atom or forms a double bond with R 1; R is hydrogen or lower alkyl; R_ and R. each represent a hydrogen atom, a lower alkyl radical, a phenyl radical, optionally substituted by halogen, a nitro, hydroxyl, carboxyl, halosulfonyl or trifluoromethyl group, a lower alkyl, lower alkoocy, lower carbalkoxy-alkyl or lower alkanylamido radical or is an aromatic heterocyclic radical, and R_ is a hydroxyl group or forms a double bond ^{with Λ,} as well as their addition salts with acids. 2, 5,7 ~ Diphenyl-7-hydroxy-2,3,5,6-tetrahydro (3,2a) thiazolpyrimidine and its addition salts with acids. 009883 / 2.272 _ 2033143 3. 5-Phenyl-7-hydroxy - ^, 3,5,6,7-pentahydro- (3, 2a) thiazole pyrimidine and its addition salts with satires. 4. 5,7-Diphenyl-2,3,5-trihydro (3.2a) thiazol-pyrimidine and its additive salts with acids. 5 x 6,8-diphenyl-2,3 »4,6-tetrahydro-1,3 (3.2a) thiazine-pyrimidine and its addition salts with acids. 6. 6-Phenyl-8-hydroxy-2,3 »4,6,7,8-hexahydro (3.2a) thiazine pyrimidine and its addition salts with acids 7 x 5-phenyl-7 (3'-trifluoromethyl-phenyl) -7-hydroxy-2,3,5,6-tetrahydro- (3,2a) thiazole-pyrimidine and its addition salts with acids. 8. 5 f 5,7-trimethyl-7-hydroxy-2,3,6-trihydro- (3,2e) thiazole pyrimidine and its addition salts with acids. 9. 5 (2-Clilor-phenyl) -7-phenyl-7-hydroxy-2,3,5,6-tetrahydro- (3 »2a) thiaEol-pyrimidine and its addition salts with acids. 10. 5-Phenyl-7 (3x -trifluoromethyl-phenyl) -2,3,5-trihydro- (3,2a) -thiazol-pyrimidine and its addition salts with acids. 11 · 5-Hienyl-7 (3'-chloro-phenyl) -7-hydroxy-2, 3,5 »6-tetrahydro- (3,2) -thiazol-pyrimidine, and its addition salts with acids. 009883/2272 12. 5 (4'-methoxyphenyl) -7-phenyl-7-hydroxy-2,3 »5» .6-tetrahydro- (3,2a) thiazol-pyrimidine and its addition salts with acids. 13. 5-methyl-7-hydroxy-2,3,5,6,7-pentahydro- (3,2a7thiazol-pyrimidine and its addition salts with acids. 14. 5-Phenyl-7 (3'-chloro-phenyl) -2,3,5-trihydro- (3,2a) thiazole pyrimidine and its addition salts with acids. 15. 5 (2'-chloro-phenyl) -7-phenyl-2,3,5-trihydro- (3,2a) thiazole pyrimidine and its addition salts with acids. 16. 5 (.4 · -Methoxyphenyl) -7-phenyl-2,3,5-trihydro- (3, 2a) thiazole pyrimidine and its addition salts with acids. 17.5 (4'-Chloro-phenyl) -7-phenyl-7-hydroxy-2,3,5,6-tetrahydro- (312a) thiazole-pyrimidine and its addition salts with acids. 18. 5 (3 • -chlorophenyl) -7-phenyl-7-hydroxy-2,3 »5,6-tetrahydro- (3,2a) thiazole-pyrimidine and its addition salts with acids. .19. 5-phenyl-7 (3'-ethoxyphenyl) -7-hydroxy-2,3,5,6-tetrahydro- (3,2a) thiazol-pyrimidine and its addition salts with acids. 20. 5 (2 ^f- Thionyl) -7-phenyl-7-hydroxy-2,3,5,6-tetrahydro- (3 »2a) -thiazol-pyrimidine and its addition salts with acids. 21. 7-Methyl-7-hydroxy-2,315 »5,6-ptntahydro- (3.2a) thiaüol-pyri- 003883/2272 2033H5 midin and its addition salts with acids. 22. 5-p-Tolyl-7-phenyl-2,3,5-trihydro- (3 _f 2a) thiazol-pyrimidine and its addition salts with acids. 23. 5 (2'-Bromo-phenyl) -7-phenyl-7-hydroxy-2,3,5,6-tetrahydro- (3,2a) thiazole-pyrimidine and its addition salts with acids. 24. 5-Phenyl (4- '-bromophenyl) -7-hydroxy-2,3,5,6-tetrahydro- (3,2a) thiazol-pyrimidine and its addition salts with acids. 25. 5-Phenyl-7 (4 x -bromophenyl) -2,3,5-trihydro- (3,2a) thiazole pyrimidine and its addition salts with acids. 26. 5-Phenyl-7-methyl-2,3,5-trihydro- (3,2a) thiazol-pyrimidine and its addition salts with acids. 27. 5 (2 · -Bromo-phenyl) -7-phenyl-2,3,5-trihydro- (3 »2a) thiazole pyrimidine and its addition salts with acids. 28., 5-Phenyl-7 (2M; hienyl) -2,3,5-trihydro- (3,2a) thiazol-pyrimi and its addition salts with acids 29. 5-Phenyl-7 C 3 * -acetamido-phenyl) -7 ~ hydroxy-g, 3,5,6-tetrahydro- (3.2a) thiazol-pyrimidine and Saesen AMition salsa with Acids. 5-Ph "nyl-7C3 ^I pyridyl) -7-hydro3cy-2 _f 3,5,6-.1; ttraliyaroC3,2a)" 009883/2272 < 2033U5 taiazol-pyrimidine and its addition salts with acids. 31. 5-Pheny1-7 (3'-nitro-phenyl) -7-hydroxy-2,3> 5 ₁ 6-tetrahydro- (3,2a) thiazol-pyrimidine and its addition salts with acids. 32. 5 (3'-pyridyl) -7-phenyl-7- ^ hydroxy-2,3 , 5,6-tetrahydro- (3 »2a) thiazol-pyrimidine and its addition salts with acids. pyrimidine and its additives with acids. 34. 5-Phenyl-7 (4'-hydroaqr-phenyl) -2 _f 3f5-trihydro- (3 »2a) * hi * Bolpyrimidine and its addition salts with acids. 35. 5-Diphanyl-5-ethyl-2,3-dihydro- (3 | 2a) thi * eol «-pyriKidin and its addition salts bit acids. 36. 5-Phenyl-7 (3 ^l -n-butoxy-pnenyl) -2 _t 3,5-triliydro- (3 _t 2a) tliiazole- # pyrimidine and its addition salts with acids. 37.5 (3 ¹ I ■ 4 ¹ , 5 «-trimethoxyphenyl) -7-phenyl-2,3f5-trihydro- (312a) thiazol-pyrlBidine and its addition salts with acids. 38. 5-Phenyl-7 (3'-fluorosulfonyl-phenyl) -7-bydroiy-2 _t 3 _f 5,6-tetra hydro- (3i2a) thiazol-pyriaidin and its addition salts with Acids. 39. 5-phenyl-7 (2 ^l -carbäthoxyaetnyl-phenyl) -2 _> 35-trinydro- (3.2a) - 009883/2772 "BAD ORIGINAL 2033U5 thiazol-pyrimidine and its addition salts with acids. 40. 5-Phenyl-7 (3 ^f -fluorosulfonyl-phenyl) -2,3,5-trihydro- (2,2a) -thiazol-pyrimidine and its addition salts with acids. 41. 5 (2'-thienyl) -7-phenyl-2,3,5-trihydro- (3,2a) thiazol-pyrimidine and its addition salts with acids. 42. 5-Phenyl-7 (3'-nitro-phenyl) -2,3,5-trihydro- (3,2a) thiazole pyrimidine and its addition salts with acids. 43 • S-phenyl-T-methyl-T-hydroxy ^, 3,5,6-tetrahydro- (3,2a) thiazole pyrimidine and its addition salts with acids. 44. Process for the preparation of the compounds of claims 1-43, characterized in that a sulfur-containing heterocyclic imine of the general formula sy I j (ir) (cH ₂ ) _n m aiit an oC-unsaturated carbonyl compound of the general formula E ₉ - C = CH - Q - R. '■ ■ ² 11-4- (Hl) R ₁ 0 in which n, E ₁ , R ₃ and R ^ have the above meaning, condensed and optionally with an acid to form the. converts the corresponding salt. 009 883/22 7 2 45. The method according to claim 44, characterized in that the imine is used in the form of its salt and in situ by an alkaline compound is released. 46. The method according to claim 44 or 45 »characterized in that that the condensation is carried out in an organic solvent. 47. The method according to any one of claims 44-46, characterized in that that the condensation is carried out below 70 ° C. and that a compound (I) is obtained in which R is hydrogen atom and R, are a hydroxyl group. 48. The method according to any one of claims 44-46, characterized in that the condensation is carried out below 70 C and that a compound (I) is obtained in which R and R,
together form a double bond. 49. The method according to claim 47, characterized in that the compound obtained (I), in which R and R, together one
Form double bond, converts it into the corresponding dehydrated compound by heating to above 7O ^{0 C.} 50. The method according to claim 49, characterized in that, Heating over a salt of the compound to be dehydrated ' is carried out. 51. Process for the preparation of the compounds of claims 00 98 83/2272 1-43 »characterized essentially by the description of the examples. 52. Medicinal product, characterized in that there is a compound of claims 1-43 and a pharmaceutically acceptable one Contains carrier substance. 009883/2272